Electrochemical nucleophilic benzylic C(sp³)-H functionalization Alexander P. Atkins 1 , Joseph A. Tate 2 and Alastair J. J. Lennox 1 * 1 University of Bristol, UK, 2 Syngenta, UK The development of selective C(sp 3 )—H functionalization reactions is necessary for improved step-, time- and waste-efficiency in synthetic chemistry. Unfunctionalized benzylic C(sp 3 )—H bonds are found in pharmaceutical and agrochemical active ingredients but are also prone to enzymatic oxidation. 1 Recently, electrochemistry has been demonstrated as a means to selectively functionalize benzylic C(sp 3 )—H bonds to produce new carbon— carbon and carbon—heteroatom bonds. 2 Anodic oxidation negates the need for traditional chemical oxidants and facilitates the coupling of electrochemically generated intermediates with inexpensive feedstock nucleophiles that can be used to increase molecular complexity or resistance to enzymatic oxidation. This work describes the use of electrochemical C(sp 3 )—H oxidation to generate benzylic cations that can be captured by a series of nucleophiles to afford higher value products. For the first time, carboxylic acids are demonstrated as an inexpensive source of nucleophile for C—O carboxylation and a means to access functionalized benzylic esters. 3 This method is applicable to a range of benzylic coupling partners, produces hydrogen gas as the sole by-product, and can be scaled up to gram-scale using flow electrochemistry. Fluoride sources can also be employed as the nucleophile to afford the corresponding benzyl fluorides. Stability studies indicate that primary benzyl fluorides are a more stable and therefore suitable target than secondary and tertiary benzyl fluorides. Precise control of the electrolysis waveform facilitates access to the more difficult primary benzyl fluorides which is demonstrated on a selection of primary benzylic substrates.
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References 1. Xie, L.; Chen, K.; Cui, H.; Wan, N.; Cui, B.; Han, W.; Chen, Y. ChemBioChem., 2020, 21 (13), 1820−1825. 2. Selected examples: Hou, Z.; Liu, D.; Xiong, P.; Lai, X.; Song, J.; Xu, H., Angew. Chem., Int. Ed., 2021, 60 (6), 2943−2947., Wang, H.; Liang, K.; Xiong, W.; Samanta, S.; Li, W.; Lei, A., Sci. Adv. 2020, 6 (20), 1-7., H. Gao, X. Chen, P.-L. Wang, M.-M. Shi, L.-L. Shang, H.-Y. Guo, H. Li and P. Li, Org. Chem. Front., 2022, 9, 1911–1916. 3. A. P. Atkins, A. C. Rowett, D. M. Heard, J. A. Tate, A. J. J. Lennox, Organic Letters, 2022, 24(28), 5105 5108.
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